Method of administering a therapeutically active substance

ABSTRACT

A method for administering a therapeutically active component including a non-adioactive drug to a target tissue in a subject includes the steps of: (a) providing a brachytherapy seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge); (b) providing a brachytherapy implantation instrument comprising at least one brachytherapy implantation needle having a bore having an interior diameter of less than about 2.7 millimeters (10 gauge), and being adapted to accept the brachytherapy seed into the bore of the at least one brachytherapy implantation needle and deliver the accepted implantation device into a target tissue; (c) introducing the brachytherapy seed into the bore of the at least one implantation needle of the brachytherapy implantation instrument; (d) introducing at least a portion of the at least one brachytherapy implantation needle into a target tissue in the subject; and (e) actuating the brachytherapy implantation instrument such that the brachytherapy seed is delivered through the bore of the brachytherapy implantation needle into the target tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority of U.S. provisionalapplication No. 60/249,128 filed Nov. 16, 2000.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] Not applicable.

FIELD OF THE INVENTION

[0003] The invention relates generally to the fields of medicine anddelivery of therapeutically active substances. More particularly, theinvention relates to implantable brachytherapy devices.

BACKGROUND

[0004] Radioactive seed therapy, commonly referred to as brachytherapy,is an established technique for treating various medical conditions,most notably prostate cancer. In a typical application of brachytherapyfor treating prostate cancer, about 50-150 small seeds containing aradioisotope that emits a relatively short-acting type of radiation aresurgically implanted in the diseased tissue. Because the seeds arelocalized near the diseased tissue, the radiation they emit is therebyconcentrated on the cancerous cells and not on distantly located healthytissue. In this respect, brachytherapy is advantageous over conventionalexternal beam radiation.

[0005] A number of devices have been employed to implant radioactiveseeds into tissues. See, e.g., U.S. Pat. Nos. 2,269,963 to Wappler;4,402,308 to Scott; 5,860,909 to Mick; and 6,007,474 to Rydell. In atypical protocol for treating prostate cancer, an implantation devicehaving a specialized needle is inserted through the skin between therectum and scrotum into the prostate to deliver radioactive seeds to theprostate. The needle can be repositioned or a new needle used for othersites in the prostate where seeds are to be implanted. Typically, 20-40needles are used to deliver between about 50-150 seeds per prostate. Arectal ultrasound probe is used to track the position of the needles.Once the end of a given needle is positioned in a desired location, aseed is forced down the bore of the needle so that it becomes lodged atthat location.

[0006] As the seeds are implanted in the prostate as desired, theneedles are removed from the patient. Over the ensuing several monthsthe radiation emitted from the seeds kills the cancerous cells. Surgicalremoval of the seeds is usually not necessary because the type ofradioisotope generally used decays over the several month period so thatvery little radiation is emitted from the seeds after this time.

[0007] Currently marketed radioactive seeds take the form of a capsuleencapsulating a radioisotope. See, e.g., Symmetra® I-125 (Bebig GmbH,Germany); IoGold™ I-125 and IoGold™ Pd-103 (North American Scientific,Inc., Chatsworth, Calif.); Best® I-125 and Best® Pd-103 (BestIndustries, Springfield, Va.); Brachyseed® I-125 (Draximage, Inc.,Canada); Intersource® Pd-103 (International Brachytherapy, Belgium);Oncoseed® I-125 (Nycomed Amersham, UK); STM 1250 I-125 (SourcetechMedical, Carol Stream, Ill.); Pharmaseed® I-125 (Syncor, Woodland Hills,Calif.); Prostaseed™ I-125 (Urocor, Oklahoma City, Okla.); and I-plant®I-125 (Implant Sciences Wakefield, Mass.). The capsule of these seeds ismade of a biocompatible substance such as titanium or stainless steel,and is tightly sealed to prevent leaching of the radioisotope. Thecapsule is sized to fit down the bore of one of the needles used in theimplantation device. Since most such needles are about 18 gauge, thecapsule typically has a diameter of about 0.8 mm and a length of about4.5 mm.

[0008] The two radioisotopes most commonly used in prostatebrachytherapy seeds are iodine (I-125) and palladium (Pd-103). Both emitlow energy irradiation and have half-life characteristics ideal fortreating tumors. For example, I-125 seeds decay at a rate of 50% every60 days, so that using typical starting doses their radioactivity isalmost exhausted after ten months. Pd-103 seeds decay even more quickly,losing half their energy every 17 days so that they are nearly inertafter only 3 months.

[0009] Radioactive brachytherapy seeds may also contain othercomponents. For example, to assist in tracking their proper placementusing standard X-ray imaging techniques, such seeds may contain aradiopaque marker. Markers are typically made of high atomic number(i.e., “high Z”) elements or alloys or mixtures containing suchelements. Examples of these include platinum, iridium, rhenium, gold,tantalum, lead, bismuth alloys, indium alloys, solder or other alloyswith low melting points, tungsten, and silver. Many radiopaque markersare currently being marketed including: platinum/iridium markers(Draximage, Inc. and International Brachytherapy), gold rods (BebigGmbH), gold/copper alloy markers (North American Scientific), palladiumrods (Syncor), tungsten markers (Best Industries), silver rods (NycomedAmersham), silver spheres (International Isotopes Inc. and Urocor), andsilver wire (Implant Sciences Corp.). Other radiopaque markers includepolymers impregnated with various substances (see, e.g., U.S. Pat. No.6,077,880).

[0010] A number of different U.S. patents disclose technology relatingto brachytherapy. For example, U.S. Pat. No. 3,351,049 to Lawrencediscloses the use of a low-energy X-ray-emitting interstitial implant asa brachytherapy source. In addition, U.S. Pat. Nos. 4,323,055 toKubiatowicz; 4,702,228 to Russell; 4,891,165 to Suthanthiran; 5,405,309to Carden; 5,713,828 to Coniglione; 5,997,463 to Cutrer; 6,066,083 toSlater; and 6,074,337 to Tucker disclose technologies relating tobrachytherapy devices.

SUMMARY

[0011] The invention relates to a brachytherapy seed that includes adrug or other therapeutically active substance that can be delivered toa subject upon implantation into the subject through the bore of abrachytherapy implantation needle. Because the brachytherapy seeds ofthe invention can be sized and shaped to fit through the bore of abrachytherapy implantation needle, they are suitable for use withbrachytherapy seed implantation instruments such as an implant needle, aHenschke, Scott, or Mick applicator, or a like device such as a RoyalMarsden gold grain gun. A drug or other therapeutically active substancecan be included in the seed in addition to, or as an alternative to, aradioisotope. A drug or other therapeutically active substance can alsobe associated with a biodegradable component so that its rate of releasein the implantation site can be controlled according to the rate thatthe biodegradable substance decomposes at the implantation site. Thus,like conventional radioactive brachytherapy seeds, the seeds within theinvention can be precisely implanted in many different target tissueswithout the need for invasive surgery. And similar to the radiationemitted from conventional brachytherapy seeds, the therapeuticallyactive substance included within a seed of the invention can bedelivered in a controlled fashion over a relatively long period of time(e.g., weeks, months, or longer periods). Moreover, becauseconcentrations of the therapeutically active substance will be greaterat the implantation site (e.g., the diseased tissue), any potentialdeleterious effect of the therapeutically active substance on healthytissue located away from the implantation site will be reduced.

[0012] Depending on the particular application, the brachytherapy seedsof the present invention offer other advantages. Among these, forexample, compared to conventional systemic administration (e.g., oral orintravenous delivery) of therapeutically active substances, thebrachytherapy seeds of the invention can provide higher and moreconsistent concentrations of a therapeutically active substance to atarget tissue. They can also eliminate the need for repeated injectionsas well as circumvent delivery problems such as where a target tissuelacks an intact vascular supply (e.g., a target tissue whose blood flowmay be compromised) or is otherwise sequestered from the blood supply(e.g., via the blood-brain barrier of the central nervous system). Insome versions of the seeds of the invention that do not contain aradioisotope (e.g., those having only the therapeutically activesubstance and biodegradable component), after the therapeutically activesubstance is completely released and the biodegradable component isfully decomposed, no foreign device will remain at the implantationsite.

[0013] Accordingly, the invention features methods for administering atherapeutically active component to a target tissue in a subject. Onesuch method includes the steps of: providing a brachytherapy seedincluding a biocompatible component, a therapeutically active componentincluding a non-radioactive drug, and a radiopaque marker, thebiocompatible component being (a) physically associated with atherapeutically active component and (b) in contact with the radiopaquemarker, wherein the brachytherapy seed has a size and shape suitable forpassing through the bore of a needle having an interior diameter of lessthan about 2.7 millimeters (10 gauge); providing a brachytherapyimplantation instrument including at least one brachytherapyimplantation needle having a bore having an interior diameter of lessthan about 2.7 millimeters (10 gauge), and being adapted to accept thebrachytherapy seed into the bore of the at least one brachytherapyimplantation needle and deliver the accepted implantation device into atarget tissue; introducing the brachytherapy seed into the bore of theat least one needle of the brachytherapy implantation instrument;introducing at least a portion of the at least one brachytherapyimplantation needle into a target tissue in the subject; and actuatingthe brachytherapy implantation instrument such that the brachytherapyseed is delivered through the bore of the brachytherapy implantationneedle into the target tissue.

[0014] Another method within the invention for administering atherapeutically active component to a target tissue in a subjectincludes the steps of: providing a brachytherapy seed including a sealedcontainer, and a non-metal biocompatible component, and atherapeutically active component including a non-radioactive drug, thebiocompatible component being physically associated with thetherapeutically active component to form a combination product; and thesealed container being made of a non-biodegradable substance, housing aradioisotope, and being at least partially coated with the combinationproduct, wherein the brachytherapy seed having a size and shape suitablefor passing through the bore of a needle having an interior diameter ofless than about 2.7 millimeters (10 gauge); providing a brachytherapyimplantation instrument including at least one brachytherapyimplantation needle having a bore having an interior diameter of lessthan about 2.7 millimeters (10 gauge), and being adapted to accept thebrachytherapy seed into the bore of the at least one brachytherapyimplantation needle and deliver the accepted implantation device into atarget tissue; introducing the brachytherapy seed into the bore of theat least one needle of the brachytherapy implantation instrument;introducing at least a portion of the at least one brachytherapyimplantation needle into a target tissue in the subject; and actuatingthe brachytherapy implantation instrument such that the brachtherapyseed is delivered through the bore of the brachytherapy implantationneedle into the target tissue.

[0015] In the foregoing methods, the biocompatible component can bebiodegradable and include a polymer such as poly(bis(p-carboxyphenoxy)propane anhydride); poly(bis(p-carboxy) methane anhydride);poly(D,L-lactic-coglycolic acid); poly(isobutylcyanoacrylate); acopolymer of poly-carboxyphenoxypropane and sebacic acid; open cellpolylactic acid; a co-polymer of a poly-fatty acid dimer and sebacicacid; poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid;polyisophthalic acid; polydodecanedioic acid; or other polymersdescribed below.

[0016] The therapeutically active component can include a drug such asstimulating and growth factors; gene vectors; viral vectors;anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents;transforming agents; apoptosis-inducing agents; radiosensitizers;radioprotectants; hormones; enzymes; antibiotics; antiviral agents;mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies;or antigens. For example, the drug can be an anti-neoplastic agent suchas paclitaxel, 5-fluorouracil, or cisplatin. It can also be aradiosensitizing agent such as 5-fluorouracil, etanidazole,tirapazamine, BUdR, or IUdR.

[0017] The radiopaque marker can include platinum, iridium, rhenium,gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaquepolymer. Radioisotopes for use in the invention can include ¹²⁵I and¹⁰³Pd.

[0018] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting. Other features and advantages of the invention will beapparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The invention is pointed out with particularity in the appendedclaims. The above and further advantages of this invention may be betterunderstood by referring to the following description taken inconjunction with the accompanying drawings, in which:

[0020]FIG. 1 is a schematic side view of a cylindrically shapedbrachytherapy seed of the invention.

[0021]FIG. 2 is a schematic side view of a hollow tube-shapedbrachytherapy seed of the invention.

[0022] FIGS. 3A-3G are schematic side views of several versions ofbrachytherapy seeds within the invention that include a radiopaquemarker.

[0023]FIG. 4A is a schematic view of a brachytherapy seed of theinvention having a sealed container housing a radioisotope partiallycoated by a therapeutically active component and a biocompatiblecomponent.

[0024]FIG. 4B is a cross-sectional view of a brachytherapy seed of theinvention having a sealed container housing a radioisotope completelycoated by a therapeutically active component and a biocompatiblecomponent.

[0025]FIG. 5A is a schematic view of a flaccid chain of severalbrachytherapy seeds conjoined with several spacer elements.

[0026]FIG. 5B is a schematic view of a rigid chain of severalbrachytherapy seeds conjoined with several spacer elements.

DETAILED DESCRIPTION

[0027] The invention encompasses compositions and methods relating toimplantable brachytherapy seeds including a biocompatible componentassociated with a therapeutically active substance. Referring to thedrawings there are illustrated various different embodiments of thebrachytherapy seeds of the invention. In FIG. 1, there is shown abrachytherapy seed 10 composed of a biocompatible component 12associated with a therapeutically active component 14 (schematicallyshown as small circles or spheres). As illustrated, the therapeuticallyactive component 14 is present as a plurality of small particlesdispersed throughout a matrix consisting of the biocompatible component12. The mixture of the components 12 and 14 is formed into thecylindrically shaped brachytherapy seed 10.

[0028] The brachytherapy seed 10 shown in FIG. 1 has a size and shapesuitable for passing through the bore of a brachytherapy implantationneedle. Although the bore can be any size compatible with brachytherapymethods, in order to minimize damage to tissue, the bore preferably hasan interior diameter of between about 0.01 and 10 mm (e.g., 0.009, 0.01,0.02, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3, 4, 5, 6, 7, 8, 9, 10, or 11 mm). For use with 10 gauge orless brachytherapy implantation needles, seed 10 has a size and shapethat can pass through a bore having a diameter of less than about 2.7millimeters (i.e., the interior diameter of a standard 10 gaugebrachytherapy implantation needle). For smaller needles such as 15 and18 gauge needles, seed 10 has a size and shape that can pass throughbores having an interior diameter of less than about 1.4 millimeters(e.g., 1.40, 1.39, 1.38, 1.37, 1.36, 1.35, or 1.34 mm) or less thanabout 0.84 millimeters (e.g., 0.86, 0.85, 0.84, 0.83, 0.82, 0.81, 0.80mm), respectively.

[0029] Although there is no lower limit as to how small any dimension ofseed 10 can be, in many applications, those that are not able to passthrough bores smaller than 0.3 mm are preferred. For example, in manyapplications where it is desirable for the implanted brachytherapy seedsto maintain their orientation in the tissue, the seed 10 should be largeenough to stayed lodged at the site of implantation in the desiredorientation for a relatively long period, larger seeds are preferred. Insome cases, the selection of materials for use in the seed 10 willeffect its size. For instance, in versions of the seed 10 where thebiocompatible component 12 is a stainless steel or titanium capsule, thewalls of the capsule may need to be greater than a certain minimum sizein order to maintain the structural integrity of the seed 10. Inaddition, in some applications, the seed 10 should also be large enoughto carry a sufficient amount of the therapeutically active component 14to be therapeutically active (i.e., a therapeutically effective amountor an amount that exerts a desired medically beneficial effect). Inorder facilitate the passage of seed 10 through the bore of a needlewhile preventing jamming of the brachytherapy implantation needle bore(e.g., caused by clumping of several seeds), it is also preferred thatthe diameter of seed 10 be just slightly less than the diameter of thebore of the needle (e.g., 0.5-5% less).

[0030] For use with the needles used in many conventional brachytherapyseed implantation devices, brachytherapy seeds shaped into a cylinder(or rod) having a diameter of between about 0.8 to 3 millimeters (e.g.,0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, or 3.1 mm) and alength of between about 4 to 10 millimeters (e.g., 3.9, 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6, or 6.1 mm) are preferred. Because many conventionalbrachytherapy seed applicators make use of brachytherapy implantationneedles about 17 to 18 gauge in size, cylindrically shaped brachytherapyseeds having a diameter of between about 0.8 and 1.1 mm (e.g, 0.79, 0.8,0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92,0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04,1.05, 1.06, 1.07, 1.08, 1.09, 1.1, and 1.11 mm) and a length greaterthan the diameter (e.g., 2-10 mm) are preferred for use with suchapplicators. In particular, because many conventional brachytherapy seedapplicators are designed to accept conventional radioactivebrachytherapy seeds that have a diameter of about 0.8 millimeters and alength of about 4.5 millimeters, brachytherapy seeds within theinvention of similar size are especially preferred.

[0031] Brachytherapy seeds within the invention are also not limited tothose being cylindrical in shape (e.g., seed 10 shown in FIG. 1), butrather can be any shape suitable for passing through the bore of aneedle. For example, in many cases, seeds within the invention can becuboid, spheroid, ovoid, ellipsoid, irregularly shaped, etc. The ends ofthe seeds can be rounded, squared, tapered, conical, convex, concave,scalloped, angular, or otherwise-shaped. The brachytherapy seeds withinthe invention can be solid as shown in FIG. 1, but can also have one ormore cavities or pores (e.g., to increase the surface area of the seedexposed to the target tissue). As one example, as illustrated in FIG. 2,a brachytherapy seed 10 of the invention is shaped into a hollow tube 18having a cylindrical cavity 20. In preferred versions of seed 10,cylindrical cavity 20 is sized to accept and envelop a standard-sizedbrachytherapy seed (e.g., one having a diameter of about 0.8 mm and alength of about 4.5 mm). For use, the seed 10 can be placed over thestandard-sized brachytherapy seed, and introduced into the bore of aneedle (sized to accept the enveloped seed) for implantation into atarget tissue. The seed 10 shown in FIG. 2 can also be used alonewithout being placed over a standard-sized brachytherapy seed, e.g., toincrease the surface area exposed in the site of implantation. Hollowtube 18 can have any wall thickness or length suitable for wholly orpartially enveloping a standard-sized brachytherapy seed and passingthrough the bore of a needle. Preferably it has a wall thickness betweenabout 0.01 and 0.1 mm (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07,0.08, 0.09, 0.1 mm) and a length of between about 1 to 4.5 mm (e.g., 1,1.5, 2, 2.5, 3, 3.5, 4, and 4.5 mm).

[0032] Referring again to FIGS. 1 and 2, biocompatible component 12 canbe composed of any material suitable for implantation in a target tissuein an animal subject (e.g., a mammal such as a human patient) that canbe associated with therapeutically active component 14 such that all orpart of the therapeutically active component 14 will be delivered to thetarget tissue when the brachytherapy seed 10 is introduced into theimplantation site. A number of materials suitable for use a component 12are known. See, e.g., Biomaterials Engineering and Devices: HumanApplications: Fundamentals and Vascular and Carrier Applications, DonaldL. Wise et al. (eds), Humana Press, 2000; Biomaterials Science: AnIntroduction to Materials in Medicine, Buddy D. Ratner et al. (eds.),Academic Press, 1997; and Biomaterials and Bioengineering Handbook,Donald L. Wise, Marcel Dekker, 2000.

[0033] As a representative example, the biocompatible component 12 canbe made of a substance other than metal (i.e., a non-metal biocompatiblecomponent). An exemplary non-metal biocompatible component is abiodegradable polymer that can act as a carrier for the therapeuticallyactive component 14. Numerous such polymers are known including, e.g.,polyorthoesters, polyanhydrides, polylactides (PLA), polyglycolides(PGA), and poly(lactide-co-glycolides) (PLGA). Other suitablebiodegradable polymers include: polylactic acid, polyglycolic acid,polyL-lactide-co-glycolide, polydioxanone, poly glycolide-co-trimethylenecarbonate, poly ethylene carbonate, polyiminocarbonates,polyhydroxybutyrate, polyester-amides, and polyamino acids. Morespecific examples of suitable biodegradable polymers include:poly[bis(p-carboxyphenoxy) propane anhydride] (PCPP);poly[bis(p-carboxy) methane anhydride (PCPM); Resomer®[Poly(D,L-lactic-coglycolic acid) (PLAGA)]; poly(isobutylcyanoacrylate)(PIBCA); Biodel®, a copolymer of poly-carboxyphenoxypropane and sebacicacid (PCPP:SA); OPLA® (open cell polylactic acid); poly-fatty acid dimerand sebacic acid [P(FAD-SA)]; poly(carboxyphenoxy) hexane (PCPH);poly-1,4-phenylene dipropionic acid (PPDP); polyisophthalic acid[P(Iph-SA)]; and polydodecanedioic acid (PDD). Other polymers suitablefor use as component 12 include: polyamido-amines (PAA), poly-2-hydroxyethyl methacrylate, poly N-vinyl pyrrolidone, polymethyl methacrylate,polyvinyl alcohol, polyacrylic acid, polyacrylamide,polyethylene-co-vinyl acetate, polyethylene glycol, polymethacrylicacid, and those described in U.S. Pat. Nos. 3,625,214; 3,867,519;4,093,709; 4,391,797; and 4,767,628.

[0034] The invention is not limited to the use of any particularsubstance for use as the biocompatible component 12. Rather certainsubstances will be preferred for certain applications while others willbe preferred for other applications. A skilled artisan can select theparticular composition of the component 12 that is most suited for agiven application. For example, where the seed 10 is intended to be usedto slowly deliver the therapeutically active component 14 when implantedin a target tissue, a biocompatible and biodegradable material made upof a chemical composition of a polymer known to degrade at a desiredrate when placed under conditions similar to those encountered in theimplantation site can be selected for use as component 12. Variouscharacteristics of such biodegradable components are described, e.g., inBiomaterials Engineering and Devices: Human Applications: Fundamentalsand Vascular and Carrier Applications; Biomaterials Science : AnIntroduction to Materials in Medicine; and Biomaterials andBioengineering Handbook, supra. For example, by selecting an appropriatematerial for use as the biocompatible component 12 of the brachytherapyseed 10, the duration of release of the therapeutically active component14 from seed 10 can be varied from less than about an hour to more thanabout several months (e.g., 10 min., 30 min., 1 h., 2 h., 3 h., 6 h., 12h., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months,4 months, 5 months, 6 months, 1 year, 2 years, or 3 years).Biocompatible component 12 is not limited to being biodegradable. Forexample, component 12 can also be made of a non-biodegradable materialsuch as stainless steel or titanium. In this case, biocompatiblecomponent 12 can be coated or otherwise associated with therapeuticallyactive component 14, such that component 14 will be delivered to atarget tissue into which seed 10 is implanted. For instance, component12 might take the form of a porous stainless steel or titanium cylinderhaving a plurality of pores through its outer surface, such pores beingfilled with or otherwise in communication with the component 14 suchthat the component 14 can diffuse from the seed 10 into the environmentsurrounding the seed 10 (e.g., a target tissue).

[0035] Compositions with unknown or incompletely investigatedcharacteristics might also be used as biocompatible component 12. Thesecan be tested for suitability in a given application by conventionalclinical testing. For example, a test composition can be fashioned intoa brachytherapy seed and implanted in a laboratory animal in a selectedtarget tissue. The effects of the implanted compositions on the animalcan then be monitored over a period of time. Those that prove to bebiocompatible (e.g., not causing an undesired response such ascalcification or an allergic response) and have a desired rate ofdegradation and delivery of a therapeutically active component (ifincluded in the test seed) can thus be identified.

[0036] Therapeutically active component 14 is a material that can (a) beimplanted in a target tissue of an animal subject (e.g., a mammal suchas a human patient) to exert an effect on the animal's physiology, and(b) be associated with the biocompatible component 12 in thebrachytherapy seed 10. Myriad different substances can be used as thetherapeutically active component 14. See, e.g., Physician's DeskReference, The Merck Index, and USP DI® 2000 published by U.S.Pharmacopeia. For example, the therapeutically active component 14 caninclude a small molecule drug (e.g., a non-peptide or non-nucleicacid-based molecule with a molecular weight generally less than 5 kDa)such as a chemical with known anti-cancer properties. It can alsoinclude a drug in the form of a biologic such as a polypeptide (e.g., anantibody or a cytokine) or nucleic acid (e.g., an expression vector).Further examples as to the form that the drug can take include withoutlimitation: stimulating and growth factors; gene vectors; viral vectors;anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents;transforming agents; apoptosis-inducing agents; radiosensitizers;radioprotectants; hormones; enzymes; antibiotics; antiviral agents;mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies;and antigens.

[0037] Therapeutically active component 14 is not, however, limited toany of the above-listed compositions or uses. Rather a skilled artisancan select a particular composition of use as the therapeutically activecomponent 14 depending on the application that the brachtherapy seed 10is intended to be used for. For example, where the seed 10 is intendedto be used as a primary treatment for prostate cancer, thetherapeutically active substance 14 can include a anti-neoplastic drugsuch as paclitaxel (taxol), cisplatin, or 5-fluorouracil; or a hormonesuch as leuprolide. As another example, where the seed 10 is intended tobe used as an adjuvant to radiation treatment for prostate cancer, thetherapeutically active substance 14 can include a radio-sensitizingagent such as tirapazamine, BUdR, IUdR, or etanidazole. Becausebrachytherapy seed 10 allows in situ drug delivery to a tissue, thetherapeutically active substance 14 might in some cases include a drugthat is usually considered too toxic to treat a given condition if givensystemically, e.g., tirapazamine or camptothecin.

[0038] As indicated in the above description of the brachytherapy seed10 shown in FIGS. 1 and 2, the biocompatible component 12 is associatedwith the therapeutically active component 14. As used herein, whenreferring to the biocompatible component 12 and the therapeuticallyactive component 14, the phrase “associated with” means physicallycontacting. Thus, in the seed 10, the association of the biocompatiblecomponent 12 with the therapeutically active component 14 can take manyforms. For example, the biocompatible component 12 and thetherapeutically active component 14 can be combined into a mixture asshown in FIGS. 1 and 2. This mixture can have a uniform or non-uniformdistribution of components 12 and 14.

[0039] The brachytherapy seed 10 shown in FIG. 1 is an example of auniform mixture of components 12 and 14. The brachytherapy seed 10 ofthis example can be made by simply mixing together the biocompatiblecomponent 12 and the therapeutically active component 14 to form acombination product and then forming the product into the desired sizeand shape, e.g., using a mold.

[0040] Although the brachytherapy seeds shown in FIGS. 1 and 2 includemixture of discrete particles dispersed through a matrix consisting ofthe therapeutically active component 14, in other versions ofbrachytherapy seed 10, components 12 and 14 are combined in a singleparticle or in a larger mass without discrete particles (e.g., a pelletthe size and shape of brachytherapy seed 10). For example, biocompatiblecomponent 12 and therapeutically active component 14 can be dissolvedinto a liquid and then dried or cured to form microspheres or a largerpellet made up of a homogeneous distribution of both components 12 and14. (see, e.g., Ramirez et al., J. Microencapsulation 16:105, 1999).Microspheres can be of any size suitable for use in the invention. Forexample, they can have a diameter of about 1 to 1000 microns (e.g.,10-100 microns, 100-200 microns, 200-300 microns, 300-400 microns,400-500 microns, 500-600 microns, 600-700 microns, 700-800 microns,800-900 microns, 900-1000 microns). The skilled artisan can select thedesired size according to the properties desired and particularproperties of the microsphere constituents. In one variation of this,the microspheres are also made to include magnetic elements. Themicrospheres can then be molded or compressed together into the desiredshape and sized of brachytherapy seed 10. The larger pellet can likewisebe sculpted, extruded, molded or compressed into the desired shape andsize of brachytherapy seed 10. Alternatively, the liquid mixture ofcomponents 12 and 14 can be poured into a mold defining the shape andsize of brachytherapy seed 10, and then cured in the mold. Brachytherapyseeds having components 12 and 14 combined in a single particle or in alarger mass (rather than discrete particles of each) are advantageousfor delivering the therapeutically active component 14 into a targettissue over longer time periods.

[0041] In other embodiments of seed 10, components 12 and 14 are notnecessarily homogeneously mixed in the seed 10. Rather they can bepositioned in different areas of the seed 10. For example, components 12and 14 can separately be fashioned into discrete sections, strips,coils, tubes, etc. The discrete sections, strips, coils, tubes, etc. ofthe component 12 can then be combined (e.g., by molding together,adhering, structurally interlocking, etc.) with the discrete sections,strips, coils, tubes, etc. of the component 14 to form the seed 10. Inanother embodiment, the seed 10 shown in FIG. 2 can be modified byfilling the cylindrical cavity 20 with a hydrogel (e.g., hydrogels fromAlkermes, Cambridge, Massachusetts) including a therapeutically activesubstance, and capping off the ends of the hollow tube 18.

[0042] Many different therapeutically active substances have beenassociated with biocompatible materials for use in drug delivery systemsapart from brachytherapy seeds. These include, for example, adriamycin(Moritera et al., Invest. Ophthal. Vis. Sci. 33:3125-30, 1992);bupivicaine (Park et al., J. Controlled Release 52:179-189, 1998);camptothecin (Weingart et al., Int. J. Cancer 62:1-5, 1995); carboplatin(Chen et al., Drug Delivery 4:301-11, 1997); carmustine (Brem et al., J.Neurosurg 74:441-6, 1991; and U.S. Pat. Nos. 4,789,724 and 5,179,189);cefazolin (Park et al., J. Controlled Rel. 52:179-189, 1998); cisplatin(Yapp et al., IJROBP 39:497-504, 1997); cortisone (Tamargo et al., J.Neurooncol. 9:131-8, 1990); cyclosporine (Sanchez et al., Drug Delivery2:21-8, 1995); daunorubicin (Dash et al., J. Pharmacol. Tox. Meth.40:1-12, 1999); dexamethasone (Reinhard et al., J Contr. Rel.16:331-340, 1991); dopamine (During et al., Ann. Neurol. 25:351-6,1989); etanidazole (Yapp et al., Radiotherapy Oncol. 53:77-84, 1999);5-fluorouracil (Menei et al., Cancer 86:325-30, 1999); fluconazole(Miyamoto et al., Curr. Eye Res. 16:930-5, 1997);4-hydroxycyclophosphamide (Judy et al., J. Neurosurg. 82:481-6, 1995);ganciclovir (Kunou et al., J. Controlled Rel. 37:143-150, 1995);gentamicin (Laurentin et al., J. Orthopaed. Res. 11:256-62, 1993);heparin (Tamargo et al., J Neurooncol. 9:131-8, 1990); interleukin-12(Kuriakose et al., Head & Neck 22:57-63, 2000); naproxen (Conforti etal., J. Pharm. Pharmacol. 48:468-73, 1996); nerve growth factor(Camerata et al., Neurosurgery 30:313-19, 1992); retroviral vectorproducer cells to transfer a cytotoxic gene product (Beer et al., Adv.Drug Deliver. Rev. 27:59-66, 1997); taxol (Park et al., J. ControlledRel. 52:179-189, 1998; and Harper, E et al., Clin. Cancer Res.,5:4242-4248, 1999); tetanus toxoid (Alonso et al., Vaccine 12:299-306,1994); tetracaine hydrochloride (Ramirez et al., J. Microencap.16:105-15, 1999); tirapazamine (Yuan et al., Radiation Oncol. Investig.7:218-30, 1999); thyrotropin-releasing hormone (Kubek et al., Brain Res.809:189-97, 1998); and vaccines (Chattaraj et al., J. Controlled Rel.58:223-32, 1999). Other therapeutically active substances that can becombined with a biocompatible component include: anesthetics,angiogenesis inhibitors (e.g., Lau D. H. et al., Cancer Biother.Radiopharm. 14:31-6,1999), antibiotics (e.g., Bahk J. Y. et al., J.Urol. 163:1560-4, 2000; and Miyamoto H. et al., Current Eye Research16:930-5, 1997), antibodies (e.g., Gomez S. M. et al., Biotechnol. Prog.15:238-44, 1999), anticoagulants (e.g., Tamargo R. J. et al., J.Neurooncol. 9:131-138, 1990), antigens (e.g., Machluf M. et al., J.Pharm. Sci. 89:1550-57, 2000), anti-inflammatory agents (e.g., ReinhardC. S. et al., J. Controlled Release 16:331-40, 1991; and Tamargo R. J.et al., J. Neurosurg. 74: 956-61, 1991), antivirals,apoptosis-inhibiting agents (e.g., Macias D. et al., Anat. Embryol.(Berl) 193:533-41, 1996), cytokines (e.g., Edelman E. R. et al.,Biomaterials 12:619-26, 1991), cytotoxic agents (e.g., Berm H. et al.,J. Nueorsurg. 80:283-90, 1994; Berm H. et al., J. Neurosurg. 80:283-90,1994; Berm H. et al., Lancet 345:1008-12, 1995;Ewend M. G. et al.,Cancer Res. 56:5217-23, 1996; Fung L. K. et al., Cancer Res. 58:672-85,1998; Grossman S. et al., J. Neurosurg. 76:640-47, 1992; Kong Q. et al.,J. Surgical Oncology 69:76-82, 1998; Shikani A. H. et al., Laryngoscope110:907-17, 2000; Straw R. C. et al., J. Orthop. Res. 12:871-7, 1994;Tamargo R. J. et al., Cancer Research 53:329-33, 1993; Valtonen S. etal., Neurosurgery 41:44-9, 1997; Walter K. A. et al., Cancer Research54:2207-12, 1994; Yapp D. T. T. et al., IJROBP 39:497-504, 1997; Yapp D.T. T. et al., Anti-Cancer Drugs 9:791-796, 1998; Yapp D. T. T. et al.,IJROBP 42:413-20, 1998; and Yoshida M. et al., Biomaterials 10:16-22,1989), enzymes (e.g., Park T. G. et al., J. Control Release 55:181-91,1998), gene vectors (e.g., Hao T. et al., J. Control Release 69:249-59,2000; and Maheshwari A. et al., Mol. Ther. 2:121-30, 2000), hormones(e.g., Rosa G. D. et al., J. Control Release 69:283-95, 2000),immunosuppressants (e.g., Sanchez A. et al., Drug Delivery 2:21-8,1995), mitogens (e.g., Ertl B. et al., J. Drug Target 8:173-84, 2000),neurotransmitters (e.g., During M. J. et al., Ann Neurology 25:351-6,1989), radioprotectants (e.g., Monig H. et al., Strahlenther Onkol.166:235-41, 1990), radiosensitizers (e.g., Williams J. A. et al., IJROBP42:631-39, 1998; and Cardinale R. M. et al., Radiat. Oncol. Invest.6:63-70, 1998), stimulating and growth factors, transforming agents(e.g., Hong L. et al., Tissue Eng. 6:331-40, 2000), and viral vectors.

[0043] The foregoing combination products (i.e., at least onebiocompatible component mixed with at least one therapeutically activecomponent) can be used in the brachytherapy seeds of the invention byforming them into a size and shape suitable for passing through the boreof a needle such as one in a conventional brachytherapy seedimplantation device.

[0044] Referring now to FIGS. 3A-F, in others embodiments of theinvention, a brachytherapy seed 10 includes a biocompatible component 12associated with a therapeutically active component 14, and a radiopaquemarker 30 attached to the biocompatible component 12 and/or thetherapeutically active component 14. Radiopaque marker 30 allows for theposition of brachytherapy seed 10 to be determined using standard X-rayimaging techniques (e.g., fluoroscopy) after seed 10 has been implantedin a target tissue. Proper positioning of seed 10 and spacing of aplurality of brachytherapy seeds in a given target tissue is importantfor ensuring that the therapeutically active component 14 is deliveredadequately to the site of the disease in the target tissue.

[0045] Radiopaque marker 30 can be made of any substance that can bedetected by conventional X-ray imaging techniques. See, e.g.,Fundamentals of Diagnostic Radiology, 2d edition, William E. Brant andClyde A. Helms (eds.), Lippincott, Williams and Wilkins, 1999; PhysicalPrinciples of Medical Imaging, 2d ed., Perry Jr. Sprawls, Medical PhysicPublishing, 1995; Elements of Modem X-ray Physics, Jens Als-Nielsen andDes McMorrow, Wiley & Sons, 2001; X-ray and Neutron Reflectivity:Principles and Applications, J. Daillant et al., Springer-Verlag, 1999;Methods of X-ray and Neutron Scattering in Polymer Science, Ryoong-JoonJ. Roe, Oxford University Press, 2000; and Principles of RadiographicImaging: An Art & A Science, Richard R. Carlton, Delmar Publishers,2000. Many such substances that can be used as marker 30 are knownincluding, most notably, high atomic number (i.e., “high Z”) elements oralloys or mixtures containing such elements. Examples of these includeplatinum, iridium, rhenium, gold, tantalum, bismuth alloys, indiumalloys, solder or other alloys, tungsten and silver. Many currently usedradiopaque markers that might be adapted for use in the inventioninclude platinum/iridium markers from Draximage, Inc.; and InternationalBrachytherapy; gold rods from Bebig GmbH; gold/copper alloy markers fromNorth American Scientific, palladium rods from Syncor; tungsten markersfrom Best Industries; silver rods from Nycomed Amersham; silver spheresfrom International Isotopes Inc, and Urocor, and silver wire fromImplant Sciences Corp. Other radiopaque markers include polymersimpregnated with various substances (see, e.g., U.S. Pat. Nos.6,077,880; 6,077,880; and 5,746,998). Radiopaque polymers useful in theinvention are described in European Patent Application 894, 503 filedMay 8, 1997; European Patent Application 1,016,423 filed Dec. 29, 1999;and published PCT application WO 9605872 filed Aug. 21, 1995. Thoseradiopaque polymers that are biodegradable are preferred in applicationswhere it is desired to have the implant degrade over time in theimplantation site.

[0046] As indicated above, radiopaque marker 30 is attached to seed 10via the biocompatible component 12 and/or the therapeutically activecomponent 14. The exact manner in which radiopaque marker 30 is attachedto seed 10 can is not critical so long as (a) the seed 10 can be passedthrough the bore of a brachytherapy implantation needle and (b) theattachment allows the position of seed 10 to be readily detected byX-ray imaging. A description of some different examples of how marker 30can be associated with seed is presented in FIGS. 3A-F. In theembodiment shown in FIG. 3A, the radiopaque marker 30 in the form of aribbon, filament, strip, thread, or wire is placed in the center andalong the length of cylindrical seed 10. In FIG. 3B, the radiopaquemarker 30 takes the form of two end caps placed at both ends ofcylindrical seed 10. In the embodiment illustrated in FIG. 3C, theradiopaque marker 30 is a coil made of a radiopaque substance runningthrough the length of cylindrical seed 10 as shown. In FIG. 3D, theradiopaque marker 30 takes the form of two beads or pellets placed attwo locations along cylindrical seed 10. In the embodiment shown in FIG.3E, the radiopaque marker 30 takes the form of two bands or rings placedat two locations along the outer surface of cylindrical seed 10. In theseed 10 shown in FIG. 3F, the radiopaque marker 30 takes the form of amesh formed into cylindrical shape. In the seed 10 shown in FIG. 3G, theradiopaque marker 30 is dispersed throughout the seed in a stippledpattern.

[0047] A particularly preferred embodiment of a brachytherapy seedshaving a radiopaque marker is one in which the radiopaque markers is apolymer. In one version of this embodiment, such radiopaque polymers arecombined with a biocompatible component and a therapeutically activecomponent to form a brachytherapy seed that can be visualized by X-rayimaging. Alternatively, the radiopaque polymer can serve as thebiocompatible component. As one example of the former, microspheres madeof a radiopaque polymer are co-mingled with microspheres containing abiocompatible component and microspheres containing (e.g.,encapsulating) a therapeutically active component (or microspherescontaining both a biocompatible component and a therapeutically activecomponent). The co-mingled microspheres are then molded into aradiopaque brachytherapy seed. As another example, the radiopaquepolymer, the biocompatible component, and the therapeutically activecomponent can be mixed together into a liquid, and the liquid can becured to form a solid pellet that can be sculpted, molded, compressed,or otherwise made into the size and shape of a brachytherapy seed. Anadvantage of preparing a radiopaque brachytherapy seed in this manner isthat, after implantation, the entire seed can be visualized by X-rayimaging rather than only a portion of a seed (e.g., as occurs with seedsutilizing conventional markers).

[0048] Referring now to FIGS. 4A and 4 B, in another aspect of theinvention, a brachytherapy seed 10 includes a biocompatible component 12associated with a therapeutically active component 14, and a sealedcontainer 40 housing a radioisotope 42. Sealed container 40 is at leastpartially coated (e.g., partially coated in the version shown in FIG.4A, and completely coated in the version shown in FIG. 4B) by thebiocompatible component 12 and/or the therapeutically active component14. Sealed container 40 is similar in some respects to those employed inconventional radioactive brachytherapy seeds (e.g., those lacking abiocompatible component 12 associated with a therapeutically activecomponent 14). Thus to prevent leaching of radioisotope 42 after seed 10is implanted into a target tissue, sealed container 40 is made of anon-biodegradable substance such as titanium or stainless steel.Further, radioisotope 42 is hermetically sealed within container 40.

[0049] The exact shape of sealed container 40 is not critical as long asit can be at least partially coated with component 12 and/or 14 to forma brachytherapy seed that can fit through the bore of a brachytherapyimplantation needle. It can thus vary in shape from cylindrical (asshown in FIG. 4), cuboid, spheroid, ovoid, ellipsoid, irregularlyshaped, etc. Of more importance is the size of sealed container 40.Because the brachytherapy seed 10 containing both the sealed container40 and the biocompatible component 12 and/or therapeutically activecomponent 14 must fit through the bore of a brachytherapy implantationneedle, container 40 must be smaller than the overall size of seed 10.In the example shown in FIG. 4B, sealed container 40 is a cylindricalcannister placed down the center of the length of the rod-shaped seed 10in a coaxial fashion. Thus, where the seed 10 has a diameter of about0.8 mm and a length of about 4.5 mm, sealed container will have adiameter less than 0.8 mm (e.g., 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,0.45, 0.5, 0.55, 0.6, 0.65, 0.7, or 0.75 mm) and a length less than 4.5mm (e.g., 1, 1.5, 2, 2.5, 3, 3.5, or 4 mm). And rather than having onlya single sealed container 40 included within brachytherapy seed 10,there can be two or more such containers (e.g., 2, 3, 4, 5, 6, 7, 8, 9,10 or more) housing the radioisotope 42.

[0050] The therapeutically active agent 14 in seed 10 including thesealed container 40 can be any of those agents described above.Preferably, however, the agent 14 is selected to provide a synergisticeffect when used in combination with the radioisotope 42 to treat aparticular diseased tissue. For example, in this preferred embodiment,agent 14 can be a radiosensitizing agent such as 5-FU, etanidazole,tirapazamine, BUdR, and/or IUdR. Various combinations of substances areknown to be more effective when used in combination than when usedalone. See, e.g, Brem et al., J. Neurosurg. 80:283-290, 1994; Ewend etal., Cancer Res. 56:5217-5223, 1996; Cardinale, Radiation Oncol.Investig. 6:63-70, 1998; Yapp et al., Radiotherapy and Oncol. 53:77-84,1999; Yapp, IJROBP 39:497-504, 1997; Yuan et al., Radiation Oncol.Investig. 7:218-230, 1999; and Menei et al., Cancer 86:325-330, 1999.

[0051] Radioisotope 42 can be any substance that emits electromagneticradiation (e.g., gamma-rays or X-rays), beta-particles oralpha-particles and is suitable for use in brachytherapy seed 10.Examples of such substances include those that decay principally byelectron capture followed by X-ray emission such as palladium-103 andiodine-125; isotopes that decay by the emission of beta-particles suchas gold-198, gold-199, yttrium-90, and phosphorus-32; isotopes thatdecay with the emission of both beta-particles and gamma-rays such asiridium-192; and isotopes that decay with the emission ofalpha-particles such as americium-241. Also useful is gadolinium-157,e..g, for use in boron-neutron capture therapy, and califomium-252,rhenium-188, samarium-153, indium-111, and holmium-166. For thetreatment of prostate cancer, palladium-103 and iodine-125 are preferredas these have been the subject of much clinical investigation for thetreatment of the disease. The amount of radioactivity of radioisotope 42can vary widely. For example, when using palladium-103 or iodine-125, anexemplary amount to treat prostate cancer about 0.33 mCi and 1.5 mCi perseed if about 50-150 seeds are used at the time of implantation. Inother applications the radioactivity per seed can range from about 0.01mCi to about 100 mCi.

[0052] In one embodiment, radioisotope 42 can be mixed with and thenconfigured into microspheres, or it can be encapsulated by thebiocompatible component to form microspheres. The radioactivemicrospheres can be molded or otherwise sized and shaped into abrachytherapy seed suitable for implantation via a brachytherapyimplantation device. In one version of this embodiment, thebiocompatible component is biodegradable such that the radioisotopecontained by this component is gradually released from the seed.Alternatively, the biocompatible component and radioisotope can be mixedtogether and configured as an amorphous pellet having the size and shapeof a brachytherapy seed suitable for implantation via a brachytherapyimplantation device.

[0053] In another embodiment of the present invention as illustrated inFIGS. 5A and 5B, a plurality of brachytherapy seeds 10 may be conjoinedinto a chain 50 using a plurality of spacers 52 to connect the pluralityof seeds 10. In the embodiments shown in FIGS. 5A and 5B, a spacer 52 isused to connect two adjacent seeds 10. Spacer 52 can have any sizesuitable for use with brachytherapy seed 10. And where a plurality ofspacers are used in one chain 50, the length of each spacer 52 can bethe same or different from the other spacers 52. For many applicationsthe length of spacer 52 will vary from between about 0.5 mm to about 50mm (e.g., 0.4, 0.5, 1, 2, 3, 4,5, 5.5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, 40, 45, 50, or 51 mm). In many cases, it is important to minimizethe bunching or straying of seeds 10 to avoid over- or under-dosing ofthe target tissue by the therapeutically active component 14 and/orradioisotope 42. Thus, the length of spacer 52 should be selectedaccordingly.

[0054] Spacer 52 can be made of a biocompatible material that can beused to join two brachytherapy seeds. See, e.g., U.S. Pat. No.6,010,446. The biocompatible material can be either biodegradable ornon-biodegradable. For example, spacer 52 can be made of catgut or alike material. Spacers designed for use with conventional radioactivebrachytherapy seeds can be used in chain 50. For example, Ethicon, Inc.(Cincinnati, Ohio) manufactures the PG910 nonsterile autoclavable spacerfor Indigo (Cincinnati, Ohio) that is sold in conjunction with anExpress Seed Cartridge. In addition, Medical Device Technologies, Inc.(Gainesville, Fla.) distributes a pre-sterilized 5.5 mm long absorbablepre-cut spacer that is made of collagen (Look™, model number 1514b).Materials for use as the spacer 52 are also manufactured by SurgicalSpecialties Corp. (Reading Pa.). Where spacer 52 is made of a relativelyflexible material, the chain 50 can be relatively flaccid as shown inFIG. 5A. Where spacer 52 is made of an inflexible material, chain 50will be rigid as shown in FIG. 5B.

[0055] In some embodiments of the present invention, the spacer 52 mayinclude a radiopaque substance (e.g., a high Z material or radiopaquepolymer described above), so that spacer 52 serves both to facilitatelocating an implanted brachytherapy seed by X-ray imaging as well as tophysically join together (and/or control the distance between) two ormore seeds.

[0056] Spacer 52 can be connected to seed 10 by any means known. Forexample, spacer 52 can be connected to seed 10 by direct attachment suchas by gluing, crimping, or melting. Spacer 52 can be attached to anyportion of the seed 10. For rod or cylinder-shaped seeds 10, tofacilitate implantation, it is generally preferred that spacer 52 beattached to the ends of the seeds 10 that the ends would be adjacent toone another when the chain 50 is inserted into the barrel of abrachytherapy implantation needle. Spacer 52 and seed 10, however, neednot be physically attached to each other. Rather they can also beassociated with each other by placing each with within the lumen of atube. The tube can be used to load a brachytherapy seed implantationdevice with a plurality of spacers 52 and seeds 10 in any sequence. Forexample, the brachytherapy seed implantation device can be loaded withone (or 2, 3, 4, 5, or more) spacer 52 being interposed between everytwo seeds 10. Similarly, the brachytherapy seed implantation device canbe loaded with one (or 2, 3, 4, 5, or more) seed 10 being interposedbetween every two spacers 52.

[0057] Methods of Making Brachytherapy Seeds

[0058] Brachytherapy seeds of the invention can be made by firstproviding a biocompatible component and a therapeutically activecomponent; then physically associating the two components to form acombination product; and finally forming the combination product into aseed having a size and shape suitable for passing through the bore of abrachytherapy implantation needle (e.g., one having an interior diameterof less than about 2.7 millimeters (10 gauge)). Seeds can be formed intoa suitable size and shape by any suitable method, e.g., molding,pressing, extruding, stamping, or chopping.

[0059] Brachytherapy seeds of the invention that are associated with aradiopaque marker can be made similarly with the addition of a step ofassociating the radiopaque marker with the seed. Brachytherapy seeds ofthe invention that include a sealed container housing a radioisotope canbe made by at least partially coating the container with thebiocompatible component and therapeutically active component.

[0060] Method for Administering a Therapeutically active component to aTarget Tissue in a Subject

[0061] The brachytherapy seeds of the invention can be fashioned into asize and shape similar or identical to conventional radioactivebrachytherapy seeds. Accordingly, the brachytherapy seeds of theinvention can be implanted into a target tissue within a subject (e.g.,a human patient or a non-human animal) by adapting known methods forimplanting conventional radioactive brachytherapy seeds into a tissue.For example, the brachytherapy seeds of the present invention can beimplanted using one or more implantation needles; Henschke, Scott, orMick applicators; or a Royal Marsden gold grain gun (H. J. Hodt et al.,British J. Radiology, pp. 419-421, 1952). A number of suitableimplantation devices are described in, e.g., U.S. Pat. Nos. 2,269,963;4,402,308; 5,860,909; and 6,007,474.

[0062] Pharmacokinetics

[0063] The brachytherapy seeds of the invention can advantageously beused to selectively deliver a predetermined amount of a therapeuticallyactive substance to a target tissue. For example when a brachytherapyseed including a therapeutically active substance is implanted in aprostate, the therapeutically active substance will be released from theseed into the tissue surrounding the implantation site. The diffusion orrelease characteristics of the therapeutically active substance inrelation to the target tissue, i.e., the pharmacokinetics of thesubstance, can be modulated by selecting appropriate biocompatiblecomponents included within the seeds, and by varying the concentrationof the therapeutically active substance in each seed.

[0064] In many applications, to treat a given target tissue with atherapeutic agent it is desirable (or even ideal) to fully saturate thetarget tissue with the therapeutic agent, while avoiding under- orover-dosing the target tissue. This can be achieved by implanting thebrachytherapy seeds of the invention into a target tissue using abrachytherapy implantation device so that, e.g., a precise number ofseeds can be implanted in precise locations within the target tissue. Bypreviously calculating the rate of diffusion of the therapeuticallyactive substance under experimental conditions (e.g., using tissue fromanimal models), an appropriate dosage can be delivered to the targettissue. Because use of brachytherapy implantation devices allows thebrachytherapy seeds of the invention to be implanted in any number ofdifferent desired locations and/or patterns in a tissue, this method isadvantageous over methods where a drug or drug impregnated matrix issimply placed on the surface of a tissue or manually inserted into asurgically dissected tissue.

[0065] Other Embodiments

[0066] While the above specification contains many specifics, theseshould not be construed as limitations on the scope of the invention,but rather as examples of preferred embodiments thereof. Many othervariations are possible. For example, although the foregoing embodimentsdescribe brachytherapy seeds having a single type of therapeuticallyactive component and/or single type of radioisotope, brachytherapy seedsfor use in the methods within the invention can also have a plurality ofdifferent therapeutically active agents and/or a plurality of differentradioisotopes. Accordingly, the scope of the invention should bedetermined not by the embodiments illustrated, but by the appendedclaims and their legal equivalents.

What is claimed is:
 1. A method for administering a therapeuticallyactive component to a target tissue in a subject, the method comprisingthe steps of: providing a brachytherapy seed comprising a non-metalbiocompatible component, a therapeutically active component comprising anon-radioactive drug, and a radiopaque marker, said biocompatiblecomponent being (a) physically associated with a therapeutically activecomponent and (b) in contact with said radiopaque marker, wherein saidbrachytherapy seed has a size and shape suitable for passing through thebore of a needle having an interior diameter of less than about 2.7millimeters (10 gauge); providing a brachytherapy implantationinstrument comprising at least one brachytherapy implantation needlehaving a bore having an interior diameter of less than about 2.7millimeters (10 gauge), and being adapted to accept the brachytherapyseed into the bore of the at least one brachytherapy implantation needleand deliver the accepted implantation device into a target tissue;introducing the brachytherapy seed into the bore of the at least oneimplantation needle of the brachytherapy implantation instrument;introducing at least a portion of the at least one brachytherapyimplantation needle into a target tissue in the subject; and actuatingthe brachytherapy implantation instrument such that the brachytherapyseed is delivered through the bore of the brachytherapy implantationneedle into the target tissue.
 2. The method of claim 1, wherein thetarget tissue is a diseased tissue.
 3. The method of claim 1, whereinthe target tissue is a prostate.
 4. The method of claim 1, wherein thebiocompatible component and the therapeutically active component areformed into a plurality of microspheres.
 5. A method administering atherapeutically active component to a target tissue in a subject, themethod comprising the steps of: providing a brachytherapy seedcomprising a sealed container, and a non-metal biocompatible component,and a therapeutically active component comprising a non-radioactivedrug, said biocompatible component being physically associated with thetherapeutically active component to form a combination product; and saidsealed container being made of a nonbiodegradable substance, housing aradioisotope, and being at least partially coated with the combinationproduct, wherein said brachytherapy seed having a size and shapesuitable for passing through the bore of a needle having an interiordiameter of less than about 2.7 millimeters (10 gauge); providing abrachytherapy implantation instrument comprising at least onebrachytherapy implantation needle having a bore having an interiordiameter of less than about 2.7 millimeters (10 gauge), and beingadapted to accept the brachytherapy seed into the bore of the at leastone brachytherapy implantation needle and deliver the acceptedimplantation device into a target tissue; introducing the brachytherapyseed into the bore of the at least one implantation needle of thebrachytherapy implantation instrument; introducing at least a portion ofthe at least one brachytherapy implantation needle into a target tissuein the subject; and actuating the brachytherapy implantation instrumentsuch that the brachtherapy seed is delivered through the bore of thebrachytherapy implantation needle into the target tissue.
 6. The methodof claim 5, wherein the target tissue is a diseased tissue.
 7. Themethod of claim 5, wherein the target tissue is a prostate.
 8. Themethod of claim 5, wherein the biocompatible component and theradioactive component are formed into a plurality of microspheres.